N-aralkyl-n-(2-cyanoalkyl)-halogenated-alkanamides and their preparation



Uniwd States Patentio 2,760,971 N ARALKYL N (2 CYANOALKYL)-HALOGENA'IEgg-ALKANAMDES AND THEIR PREPARA- TIO Alexander R. Surrey, Albany, N.Y., assignor to Sterling Drug Inc., New York, N. Y., a corporation ofDelaware No Drawing. Application February 19, 1954, Serial No. 411,552

17 Claims. (Cl. 260-465) This invention relates toN-aralkyl-N-(2-cyanoalkyl)- halogenated-alkanamides and to theirpreparation.

The N-aralkyl-N-(2-cyanoalkyl)-halogenatedalkanam ides of my inventionhave the general formula Y-ON ArXN

where Ar is a member selected from the group consisting of phenyl,naphthyl, biphenylyl, furyl, pyridyl and thienyl radicals, X is a loweralkylene radical having one to four carbon atoms, Y is a loweralpha,beta-alkylene radical having two to four carbon atoms and Ac is alower halogenated-alkanoyl radical having one to four carbon atoms.These halogenated-alkanamides have valuable chemotherapeutic properties,for instance, amebacidal activity.

The radical Ar can have from one to three substituents such as halo,lower alkoxy, lower alkyl, lower alkylmercapto, lower alkylsulfonyl,nitro and di(lower alkyl)- amino. Furthermore, said substituents can bein any of.

the available positions of the Ar nucleus, and where more than onesubstituent, they can be the same or different and can be in any of thevarious position combinations relative to each other. The halosubstituents include chloro, bromo, iodo and fluoro. The loweralkoxy,-l'ower alkyl, lower alkylmercapto and lower alkylsulfonylsubstituents, and the lower alkyl radicals of said di(lower alkyl) aminosubstituent, have preferably one to six carbon atoms, including suchsubstituents as: methoxy, ethoxy,

methylenedioxy, ethylenedioxy, n-propoxy, isopropoxy;

isobutoxy, n-amoxy, n-hexoxy, and the like, when 'lo wer alkoxy; methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Z-butyl, n-amyl, n-hexyl,and the like, when'lower alkyl; methylmercapto, ethylmercapto,n-propylmercapto,

oHioH2( )H(0Ha) and the like.

The lower alpha,beta-alkylene radical Y has two to four carbon atoms,and includes such examples as I oH2cH2, -OH(0H )CHz-,CH OHCH;

| -C (CH3)2CH2, CH2CH(CH2CH2) and the like.

" The lower halogenated-alkanoyl radical Ac has one to four carbonatoms, and includes such examples as 2,760,971 Patented Aug. 28, 1956chloroformyl (chloromethanoyl), chloroacetyl (chloroethanoyl),iodoacetyl, fluoroacetyl, dichloroacetyl (dichloroethanoyl),dibromoacetyl, trichloroacetyl 2-chloropropanoyl(alpha-chloropropionyl), 3-bromopropanoyl, 2,2-diiodopropanoyl,2-bron1o-3-chloropropanoyl, 2,2-dichloropropanoyl,2,2-difluoropropanoyl, 2,2,3-trichloropropanoyl(alpha,alpha,beta-trichloropropionyl), 2-chlorobutanoyl(alpha-chlorobutyryl), 3-bromobutanoyl, 2,2- dichlorobutanoyl,3,4-dibromobutanoyl, 2,2,3-trichlorobutanoyl, 2,3,4-trichlorobutanoyl,and the like.

The compounds of my invention were prepared by reacting anN-(Z-cyanoalkyl) -substituted-alkylamine of the formula, ArXNH--YCN,with an acylating agent selected from the group consisting of thosehaving the formula Ac-halogen and (Ac)2O, where Ar, X, Y and Ac have themeanings given above. When a halogenatedalkanoyl halide, Ac-halogen, wasused, the halide halogen, i. e., the halo radical attached to thecarbonyl function, was preferably chloro, however, the other haloradicals,

i. e., bromo, iodo and fluoro also can be used. Illustra-- tions of theprocess of my invention are: the preparation ofN-(2,4-dichlorobenzyl)-N-(2-cyanoethyl)dichloroacetamide by reactingN-(2-cyanoethyl)-2,4-dichlorobenzylamine with dichloroacetyl chloride;the preparation of N- (2,4 dibromobenzyl) -N-(2-cyanopropyl)-2,3-dichloro- I propanamide by reacting N-(Z-cyanopropyl)-2,4-dibromobenzylamine with 2,3-dichloropropanoyl chloride; and thepreparation of N-(4-nitrophenethyl)-N-(2-cyanobutyl)-2,2-difiuorobutanamide by reacting N-(2-cyanobutyl)-4-.

nitrophenethylamine with 2,2-difluorobutanoic anhydride. When ahalogenated-alkanoic anhydride is used, the reaction can be carried outat room temperature or higher if necessary. When a halogenated-alkanoylhalide was used, the reaction was carried out preferably below roomtemperature, with chilling if necessary. In the preparation of achloroformamide, an N-(2-cyanoalkyl)-substituted-alkylamine, preferablyas its hydrochloride, is treated in refluxing toluene with phosgene, e.g., N-(3,4- dichlorobenzyl) -N- Z-cyanoethyl) chloroformamide byreacting N-(Z-cyanoethyl) 3,4 dichlorobenzylamine with phosgene.

The intermediate N (2 cyanoalkyl)-substituted-alkylamines of the abovegiven formula were prepared by reacting a substituted-alkylamine of theformula,

ArXNH2 where Ar and X have the meanings given above, with a2-alkenenitrile selected from the group consisting of acryare thoselonitrile and alkylated-acrylonitriles. This preparation was carried outpreferably by allowing the reactants to stand at-room temperature forabout forty-eight hours and then heating the reaction mixture on a steambath .for about one hour to drive 01f any unreacted acrylonitrile.

Illustrations of the preparation of the intermediate N-(Z-cyanoalkyl)-substituted-alkylamines are: the preparation ofN-(2-cyanoethyl)-2,4-dichlorobenzylamine by reacting2,4-dichlorobenzylamine with acrylonitrile; the preparation ofN-(Z-cyanopropyl)-3,4,5-tribromobenzylamine by reacting3,4,5-tribromobenzylamine with alpha-methylacrylonitrile; thepreparation of N-(2-cyanobutyl)-4- nitrophenethylamine withalpha-ethylacrylonitrile. 1 The following examples will furtherillustrate specific embodiments of the invention without, however,limiting it thereto.

-' EXAMPLE 1 A. N-(2-cytzn0alkyl)-substituted-alkylamines Thepreparation of the intermediate N-(Z-cyanoalkyD- g. of acrylonitrile wasleft at room temperature for two days. After the reaction mixture hadbeen heated on a steam bath for one hour to drive ofi any unreactedacrylonitrile, the product was distilled, resulting in 24.9 g. ofN-(Z-cyanoethyl)-4-isopropylbenzylamine, B. P. 100- 102" C. at 0.07 mm.,1713 1.5161.

Analysis.Calcd. for C13H18N21 NAP, 6.92. Found: NAP,6.85.

Here NAP means basic nitrogen content as determined by acetic-perchlorictitration.

Other N-(Z-cyanoethyl)-substituted-alkylamines that were preparedfollowing the procedure described above for the preparation ofN-(Z-cyanoethyl)-4-isopropylbenzylarnine using the appropriatesubstituted-alkylamine and acrylom'trile are given in Table I.

TABLE I R B. N-(substituted-alkyl) -N- (Z-cyanoalkyl-halgenatedalkanamides These N,N-disubstituted-halogenated-alkanamideswere prepared by reacting an N-(2-cyanoalky1)-substituted-alkylaminewith an acylating agent selected from the group consisting of thosehaving the formula Ac-halogen and (Ac)2O, where Ac has the meaning givenabove. There follows an illustration of such a preparation using ahalogenated-alkanoyl halide, Ac-halogen: A mixture of 20.2 g. ofN-(2-cyanoethy1)-4-isopropylbenzylarnine, 125 ml. of 1 N sodiumhydroxide solution and 100 ml. of ethylene dichloride was cooled to 0 C.in an ice-salt bath, and 14.7 g. of dichloroacetyl chloride and 50 ml.of ethylene dichloride was added slowly with stirring, the temperaturebeing kept below C. After the addition had been complete, the mixturewas stirred while allowed to warm to room temperature. The organic layerwas separated, washed with 2 N hydrochloric acid and water, treated withdecolorizing charcoal and filtered. The sol- 2O vent was removed underreduced pressure yielding 26 g. R n B? m/ Refractive Anal sis (p r ofsolid which was recrystallized once from isopropanol,

Index I yielding the product N-(Z-cyanoethyl)-N-(4-isopropyl- Calcd-Fmmd benzyl)dichloroacetamide, M. P. 107.91l1.6 C. (corr.). o 25Analysis.-Calcd. for CH1sCl2N2O: C, 57.52; H, 5.79; :i:g}:8 i 315, 30112-23 01, 22.64. Found: c, 57.79; H, 5.52; c1,22.34. H 1 124/0.9....-nn 1.5353 "iiiiifi si The same product, N-(Z-cyanoethyl)-N-(4-isopropyl-$35 gig; NAP 707 benzyl)dichloroacetamide, can be prepared by reacting4-CaH7-i- 1 7m 1. 5161 $56.92 ""5755N-(Z-cyanoethyl)-4-isopropylbenzylamine with dichloroifgggggi:13271-5273 3 13-32 2-3? no acetic anhydride instead of dichloroacetylchloride. 4-0H3 1 15:81 OtherN-benzyl-N-(Z-cyanoethyl)dichloroacetarnides gfiggggfi 20-78 that wereprepared following the procedure described H 2 ""fi above for thepreparation of N-(4-isopropylbenzyl)N-(2- 218 3 M281 5278cyanoethyl)dichloroacetarnicle, using the appropriate s-om 2 71.13231,5200 1 N-(Z-cyanoethyl)benzylamine and acylating agent, e. g., 2 5435N11-58 11-58 dichloroacetyl chloride in most instances, are given inTable II.

TABLE II R /OHaCH:ON

Anal s's ercent) R M. P./C. y 1 (p Calcd. Found 2,4-di- 1 11s. 7-118.o1K ,20.se;N,8.24 20. 8.25 4- 90.2-92.9 ClK0H ,20.86;N,8.24. 20.95;s.2377.0-79.5 0, 53. 15; H, 4.. 46; O1. 53. 02; 4. 53; 26. 26 o, 4.7. 15; H,3. 63; c1, 47. 06; 3. so; 34. e7 90.9-93.9 0,49. 55; H,3.84; N, 49. 77;3.76; 8.82 70.3-73.2 0,50. 77; H,4.87; N, 51.05; 5.19; 8.33 93.9-95.50,5599; H,5.87; N, 55. 20; s. 12;8. 12 4-0113 80.1-83.7 o, 54.. 75;11,4. 95; N, 54.43;5.22;9;93 4-N(CH:)2 93-957 0,53. 51; H, 5.45; N, 5340; 5.45; 13. 2s

'Clxonmeans hydrolyzable chlorine as determined by hydrolysis withpotassium hydroxide followed by gravimetric or amperometric method.

B. P. ISO-5C. at 0.03 mm.; solidified on standing.

Other N-(Z-cyanoalkyl) -substituted-alkylamines can be preparedaccording to the above procedure using the ap-- propriate2-alkenenitrile and substituted-alkylamine;

such compounds include N-(2-cyanoethyl)-1-naphthyl-- methylamine,N-(Z-cyanoethyl) 1 biphenylylmethylamine,N-(2-cyanoethyl)-4-n-hexylbenzylamine, N-(2-cyaIIOethyD-ZAdiiodobenzylamine, N-(2-cyanoethyl-4- nitrophenethylamine, N-2-cyanopropyl) -1 3 ,4,5triethoxyphenyl) ethylamine, N- Z-cyanopropyl-4- (2,4-dichlorophenyl)butylamine, N (Z-cyanobntyl)4-di-n-butylaminobenzylamine, N-(Z-cyanoethyl)-4-n-hexoxybenzylamine,N-(Z-cyanoethyl)-4-n-butylmercaptobenzylamine, N-(Z-cyanoethyl)-4-nbutylsulfonylbenzylamine,, N-(Z-cyanoethyl)-4-nitrobenzylamine andthe like.

haloalkanoylating agent including a monohaIoalkarmyl halide or' amonohaloalkanoic anhydride. This prepara; tion is illustrated by thefollowing preparation of N-(2,4dichlorobenzyl)-N-(2-cyanoethyl)chloroacetamide using chloroacetylchloride: A solution of 10 g. of chloroacet yl chloride in ml. ofethylene dichloride was slowly added with stirring to a cooled mixture(below 5 C.) of 17.2v g. of N-(2-cyanoethyl)-2,4-dichlorobenzylamine,100 ml. of 1 N sodium hydroxide solution and 125 ml. of ethylenedichloride. When the addition had heed completed, stirring was continuedwhile the mixture was allowed to warm up to room temperature. The layerswere separated and the organic layer was washed with 2 N hydrochloricacid,

water and then dried. Decolorizing charcoal was addedto the driedsolution, the mixture filtered and the filtrate evaporated under reducedpressure. There remained 9.5 g. of oily material which solidified oncooling. This product,N-(2,4-dichlorobenzyl)-N-(2-cyanoethyl)chloroacetamide, melted at68.5-69.9" C. (corn) N (substituted-alkyl -N- (Z-cyanoalkyl)trihalaacetamides These trihaloacetamideswere prepared by reacting anN-(Z-cyanoalkyl)-substituted-alkylamine with a trihaloacetylating agent,including a trihaloacetyl halide or a trihaloacetic anhydride. Thispreparation was carried out following the procedure described above forExample 13, for. example, using 8 g. ofN-(2-cyanoethyl)-3,4-dichlorobenzylamine and 6.5 g. of trichloroacetylchloride, there was obtainedN-(3,4-dichlorobenzy1)-N-(2-cyanoethyl)trichloroacetamide, M. P.94.898'.7 C. (corn) when recrystallized from isopropanol.

Analysis.-Calcd.-for C12H9Cl5N2O: C1, 4733; N, 7.48. Found: Cl, 47.48;N, 7.55. r

Also prepared according to the foregoing procedure were N-(4-chloroben'zyl) -N- (2-cyanoethyl) trichloroacetamide, M. P. 84.886.9C. (corn) [Analysis.Calcd. for C12H10C14N2O: C, 42.38; H, 2.97; N, 8.24.Found: C, 42.96; H, 2.63; N, 8.29]; and N-(4-isopropy1benzy1.)-N-(Z-cyanoethyl)trichloroacetamide, M. P. 47.l50.2 C. (corr.)[Analysis.Calcd. for C15H1'zCl3N2O:.-C, 51.82; H, 4.93; CI, 30.60.Found: C, 51.97; H, 4.94; Cl, 30.50.

Other N-(substituted-alkyl) -N-(2 cyanoalkyl)trihaloacetamides that canbe prepared according to'the above procedure using the appropriate N-(ZcyanOaIkyD-substituted-alkylamine and halogenatd-alkanoylating agentinclude the following:N-(2,4-dichlorobenzyl)-N-(2-cyanoalkyl)trichloroacetamide, N-(4-nbutoxybenzyl) N- (2-cyanoethyl)trichloroacetamide, N (3,4 dibromoben-Zyl )-N (2 cyanopropyl)tribromoacetamide, N (4 nhexylbenzyl) N (2'cyanobutyl)trichloroacetamide, N- 3,4,5 triiodobenzyl) N (2cyanoethyl)trichloroacetamide, N- (2,4-dichlorophenethyl) -N- (2cyanoethyl) trichloroacetamideQand the like. 5

EXAMPLE 3 These rnono'haloalkanamide's' were prepared by reacting anN-(2=cyaiioalkyl) substituted alkylamine witha mono- Analysis.-Calcd.for C12H11C13N2O: C, 47.16; H, 3.63;

NK, 9.16. Found: C, 47.25; H, 3.63; NK, 9.14.

Also prepared according to the foregoing procedure wasN-(3,4-dimethoxybenzyl)-N (2 cyanoethyl)chloroacetamide, M. P.74.479.1.C. (corn). 1

Analysis.Calcd. for C14H17C1N2O3: C, 56.64; H, 5.77; Cl, 11.96. Found:C, 56.55; H, 5.42; Cl, 12.25.

Other N-(substituted-alkylyNr (2 cyanoalkyl)monohaloalkanamides that canbe prepared according to the above procedure include'the following:N-(3,4-dichlorobenzyl)-N (2 cyanopropyl)chloroacetamide, N (4nbutoxybenzyl) -N-(2-cyanoethyl) 3 chloropropanat'nide,

N- 2,4-dichlorobenzyl) -N- 2-cyanoethyl) -4- bromobutanamide,N-(3,4-dibromobenzyl)-N-(2 cyanoethyDbromoacetamide,N-(4-n-hexylbenzyl)-N-(2-cyanobutyl)fiuoroacetamide,N-(2,4-diiodobenzyl)-N-(2 cyanoethyl)iodoacetamide,N-(2,4-dichloropheuethyl)-N-(2-cyanoethyl)- chloroacetamide, and thelike.

EXAMPLE 4 A. N-(Z-cyandethyl)furfurylamine A mixture of 9.7 g. offurfurylamine (Z-furylmethylamine) and 6.4 g. pfacrylonitrile was leftat room temperature for one week.- The reaction mixture was then A amineand N-(Z-cyanopropyl)-5-chloro-2-pyridylmethylamine. I

B. N- (2-.cyan0ethyl) N- (furfuryl) dichloroacetamide A mixture of 10 g.of N-(Z-cY'anoethyl)furfurylamine, 75 ml. of 1 Nsodium hydroxidesolution :and 75 ml. of ethylene dichloride was cooled (below 5 C.) andstirred while 9.9 g. of dichloroacetyl chloride in 25 m1. of ethylenedichloride was added slowly. When the addition had been completed,stirring was continued while the mixture was allowed to warm up to roomtemperature. The ethylene dichloride layer was separated and washedrespectively with 2 N hydrochloric acid and water, and dried.Decolorizing charcoal was added to the dried solution, the resultingmixture filtered and the filtrate evaporated under reduced pressure,yielding a light brown oily material that was further dried at 6070 C.(corn) at 0.05 mm. Hg for two hours. There was thus obtained 13.5 g. ofN-(Z-cyanoethyl)-N-(furfuryl) dichloroacetamide.

Analysis.-Calcd. for CmHmClzNzOz: C, 45.99; H, 3.86; N, 10.73. Found: C,45.44; H, 4.16; N, 10.59.

Other N- substituted-alkyl) -N- 2-cyanoethyl) dichloroacetamides thatcan be prepared according to the above procedure using the appropriatereactants are N-(Z- cyanoethyl) -N- Z-thienylrnethyl dichloroacetamide,N- (Z-cyanoethyl) N (Z-pyridylmethyl)dichloroacetamide, N- Z-cyanoethyl-N 3-1pyridylmethyl dichloroacetamide and N- (Z-cyanopropyl) -N- 5-chloro-2-pyridylmethyl) dichloroacetamide.

The N-aralkyl-N- 2-cyano alkyl -halogenated-alkan amides of theforegoing examples when administered orally to hamsters infected withEndamoeba criceti were found to completely clear the animals at druglevels below 200 mg. per kg. of body weight. Some of the compounds, forinstance, N-(2,4-dichlorobenzyl)-N-(2-cyanoethyl)- dichloroacetamide, N-3 ,4-dichlorobenzyl) -N- (2-cyanoethyl) dichloroacetamide, N-benzyl-N-2-cyanoethyl) dichloroacetarnide, N- 4-methylbenzyl -N- (2-cyanoethyl)dichloroacetamide andN-(4-chlorobenzyl)-N-(2-cyanoethyl)trichloroacetamide, have ED50 valuesbelow 50 mg. per kg. of body weight, ED50 meaning the effective dosenecessary to clear 50% of the hamsters of the vamebic infection.

I claim:

1. A compound having the formula where Ar is a member selected from thegroup consisting of phenyl, naphthyl, diphenylyl, furyl, pyridyl andthienyl radicals and such radicals substituted by from one to threesubstituents selected from the group consisting of halo, lower alkoXy,lower alkyl, lower alkylmercapto, lower alkylsulfonyl, nitro anddi(lower alkyl)amino, X is a lower alkylene radical having one to fourcarbon atoms, Y is a lower alpha,beta-alkylene radical having two tofour carbon atoms and Ac is a lower halogenatedalkanoyl radical havingone to four carbon atoms.

2. A compound having the formula (halogen) CHaCHa CN (h logen) C 0 O H(halogen) 1 3. A compound having the formula (halogen) CHaCHrCN C Et -NC O CH (halogen):

4. A compound having the formula (lower alkyl) CHzCHzCN C Hz-N C O CH(halogen);

5. compound having the formula CHzCHlCN C 0 CH (halogen) z 6. A compoundhaving the formula (halogen) CHrOHz ON -CH1-N C O CH (halogen) 3 whereAr is a member selected from the group consisting of phenyl, naphthyl,biphenylyl, furyl, pyridyl and thienyl radicals :and such radicalssubstituted by from one to three substituents selected from the groupconsisting of halo, lower alkoxy, lower alkyl, lower alkylmercapto,-

lower alkylsulfonyl, nitro and di(lower alkyl)amino, X is a loweralkylene radicalhaving one to four carbon atoms, Y is a loweralpha,beta-alkylene radical having two to four carbon atoms and Ac is alower halogenatedalkanoyl radical having one to four carbon atoms, whichcomprises reacting a compound of the formula,

with an acylating agent selected from the group consisting of thosehaving the formula Ac-halogen and (Ac) 2O.

13. A process for the preparation of a compound having the formula(halogen) CHzCHzCN (halogen) C Q C H (halogen):

which comprises reacting the correspondingN-(2-cyanoethyl)dihalobenzylamine with a dihaloacetyl halide.

14. A process for the preparation of a compound having the formula(halogen) CHQCHICN CHz-N G 0 CH (halogen) which comprises reacting thecorresponding N-(Z-cyanoethy1)halobenzylamine with a dihaloacetylhalide.

15. A process for the preparation of a compound having the formula(lower alkyl) OHOHQON C Hal-N C O CH (halogen):

which comprises reacting the correspondingN-(Z-cyanoethyl)alkylbenzylamine with a dihaloacetyl halide.

16. A process for the preparation of a compound having the formula 17. Aprocess for the preparation of a compound having the formula whichcomprises reacting the corresponding N-(2-cyanoethyl)halobenzy1aminewith a trihaloacetyl halide.

CHzCHaON @CHH/ C O OH (halogen) a CHaCHaCN which comprises reactingN-(2-cyanoethy1)benzylamine with a dihaloacetyl halide.

10 No references cited.

1. A COMPOUND HAVING THE FORMULA